Thrombocytopenia is associated with a variety of diseases and is characterized by abnormally low platelet counts in the blood often due to platelet underproduction, platelet sequestration, production of defective platelets, or increased platelet destruction. Symptoms of thrombocytopenia include, e.g., malaise, bruising (e.g., purpura), and bleeding (e.g., from the nose or gums). One example of a thrombocytopenia-associated disease is thrombotic thrombocytopenic purpura (TTP), which is a disorder characterized by extensive microscopic blood clot formation (thrombi) in small blood vessels throughout the body. If left untreated, a patient's condition can rapidly deteriorate to include severe neurological defects (e.g., stupor or coma), renal failure, stroke, and cardiac arrest. The mortality rate for untreated TTP is greater than 90%.
Thrombocytopenia-associated diseases can also result from exposure to radiation (e.g., a radiotherapy regimen), cancers, the administration of certain compounds (e.g., cytotoxic drugs), and immune responses to certain vaccines.
Thrombopoietin (TPO) is a glycosylated growth factor that stimulates the production and differentiation of megakaryocytes, the bone marrow cells that give rise to large numbers of platelets. (See, e.g., Kaushansky (2006) N. Engl. J. Med. 354(19):2034-45.) TPO binds to the c-Mpl receptor expressed on megakaryocytic progenitor cells to thus stimulate proliferation and differentiation of the cells into platelets. Paradoxically, treatment of patients with recombinant human TPO resulted in the generation of anti-TPO neutralizing antibodies that bound to and interfered with the activity of the patient's naturally occurring TPO. (See, e.g., Kuter and Begley (2002) Blood 100:3457-3469; Li et al. (2001) Blood 98:3241-3248; and Vadhan-Raj et al. (2000) Ann Intern Med 132:364-368.) Thus, there is a need for new and better treatments for patients with thrombocytopenia-associated diseases.